Albinism Associated With Torsional Nystagmus Masquerading as Spasmus Nutans

Clinical Correspondence Section Editors: Robert Avery, DO Karl C. Golnik, MD Caroline Froment, MD, PhD An-Guor Wang, MD Albinism Associated With Torsional Nystagmus Masquerading as Spasmus Nutans Helen J. Kuht, BMedSci, Rebecca J. McLean, BSc, PhD, Abdullah Aamir, MBChB, BSc, Gail D.E. Maconachie, BMedSci, PhD, Irene Gottlob, MD, FRCOphth, Mervyn G. Thomas, MBChB, PhD O culocutaneous albinism (OCA) is a genetically heterogenous disorder caused by disruption to the melanin biosynthesis pathway, affecting approximately 1 in 20,000 individuals worldwide (1). OCA has an autosomal recessive inheritance characterized by reduced pigmentation of the hair, skin, and eyes. Nonsyndromic OCA can be subdivided into 7 main types (OCA1-7), based on the genetic mutation. Ocular characteristics of OCA demonstrate significant phenotypic variability and can include iris transillumination defects (TIDs), fundus hypopigmentation, foveal hypoplasia, and optic nerve decussation defects (1,2). Nystagmus is often associated with OCA; however, it typically demonstrates a conjugate, horizontal, jerk waveform with increasing slow-phase velocities. We describe a rare presentation of intermittent torsional nystagmus in an individual with genetically confirmed OCA, initially masquerading as spasmus nutans. A 1-year-old Caucasian girl was referred to the pediatric neuro-ophthalmology clinic at Leicester Royal Infirmary, United Kingdom, with a history of intermittent nystagmus and head nodding observed from age 3 months. She was born 4 weeks prematurely with a normal delivery. There was no significant ophthalmic family history. On initial clinical examination, fine, intermittent, torsional, conjugate nystagmus and intermittent vertical The University of Leicester Ulverscroft Eye Unit (HJK, RJM, AA, GDEM, IG, MGT), Department of Neuroscience, Psychology and Behaviour, University of Leicester, RKCSB, Leicester, United Kingdom; and Health Sciences School (GDEM), Division of Ophthalmology & Orthoptics, University of Sheffield, United Kingdom. Supported by the Ulverscroft Foundation, Fight for Sight (grant ref: 5009/5010), and the Medical Research Council (MRC), London, UK (grant number: MC_PC_17171). M. G. Thomas is supported by the NIHR (CL-2017-11-003). M. G. Thomas has received consultancy fees from Leica Microsystems unrelated to this study. M. G. Thomas has received speaker honoraria from Roche. The remaining authors report no conflicts of interest. Address correspondence to: Mervyn G. Thomas, MBChB, PhD, Ulverscroft Eye Unit, Department of Neuroscience, Psychology and Behaviour, University of Leicester, Robert Kilpatrick Clinical Sciences Building (Room 516, Level 5), Leicester, LE2 7LX, United Kingdom; E-mail: [e-mail]. Kuht et al: J Neuro-Ophthalmol 2023; 43: e313-e315 head nodding were observed, with no manifest deviation on the cover test (see Supplemental Digital Content, http:// links.lww.com/WNO/A523). Slit lamp biomicroscopy revealed no apparent anterior segment abnormalities. MRI of the brain was normal. A hypermetropic prescription was issued after cycloplegic refraction (R: +4.00/-1.25 · 180, L: +4.00/-1.50 · 178). An initial clinical diagnosis of spasmus nutans was suspected because of age of presentation and the presence of intermittent high-frequency, small-amplitude nystagmus and head nodding. The patient returned on subsequent clinical visits aged 1, 5, and 10 years. Visual-evoked potential investigation identified possible asymmetry with reversing polarity on monocular stimulation. Ophthalmic assessment at age 10 years revealed best-corrected visual acuity of 0.18 logMAR (6/9.5 + 1) in both eyes and fine intermittent predominantly torsional nystagmus (see Supplementary Digital Content, http://links.lww.com/WNO/A523). The intensity of nystagmus increased on dextroversion and decreased on convergence. The patient had an abnormal head posture of a head turn and tilt to the right. A left-alternating esotropia was observed, with left inferior oblique overaction/ dissociated vertical deviation (Fig. 1A, B). Slit lamp biomicroscopy identified bilateral grade 2 iris TID and fundus hypopigmentation (Fig. 2A, B). The optic nerve appeared slightly crowded. Handheld optical coherence tomography (HH-OCT) (Leica Envisu C-class; Leica Microsystems, Wetzlar, Germany) revealed grade 2 foveal hypoplasia (Fig. 2C, D) (2). Skin pigmentation was described as fair. Subsequent ophthalmic clinic visits up to the age of 10 years confirmed the persistence of the intermittent torsional nystagmus (see Supplementary Digital Content, http:// links.lww.com/WNO/A523), and eye movement recordings (Eyelink2, SR Research, Canada) revealed infantile waveforms with a latent component (Fig. 1C). Clinical genetic testing was performed to determine the molecular diagnosis. In brief, this included the extraction of genomic DNA from a saliva sample (DNA Genotek OG-500 saliva kit, Ottawa, Canada) and performing targeted nextgeneration sequencing (NGS) using the nystagmus gene panel, testing all known nystagmus genes (3). NGS revealed one e313 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence FIG. 1. A. Left inferior oblique overaction/dissociated vertical deviation (DVD) on ocular motility assessment, when looking in dextroversion. B. DVD observed in the left eye on occlusion of the left eye. C. Original horizontal eye movement recordings showing right-beating nystagmus on covering the left eye consistent with infantile waveforms with a latent component (increasing amplitude on covering the left eye). Deflection upward represents movement to the right, whereas deflection downward represents movement to the left. Gray arrow indicates blink. RE, right eye; LE, left eye. known pathogenic heterozygous variant in TYR (NM_000372): c.238T.C: p.(Trp80Arg) in addition to the recently reported TYR pathogenic haplotype (NM_000372): c.575C.A: p.(Ser192Tyr), c.1205G.A: p.(Arg402Gln), and rs147546939 A . G (1). When the patient first presented at age 1 year, an initial diagnosis of spasmus nutans was provided. Spasmus nutans typically presents between ages 4 and 14 months with a triad of clinical features: (1) head nodding, (2) nystagmus, FIG. 2. Fundus photographs demonstrating fundus hypopigmentation in the right (A) and left (B) eye. Foveal HH-OCT of the right (C) and left (D) eye revealing grade 2 foveal hypoplasia, demonstrating the continuation of the inner retinal layers and the absence of a foveal pit but maintaining outer nuclear layer widening and outer segment lengthening. e314 and (3) torticollis. However, nystagmus associated with spasmus nutans is typically disconjugate, with different amplitude and frequency between the eyes. This does not conform with the observed conjugate nature of the nystagmus in our reported case. Furthermore, the nystagmus continued to persist to the age of 10 years. Spasmus nutans typically clinically spontaneously resolves within a few years of onset. Torsional nystagmus reported in the literature is generally associated with acquired conditions such as spaceoccupying lesions and vestibular disorders. There have been cases reported of torsional nystagmus associated with latent nystagmus in infantile esotropia, with the presence of head nodding (4). However, infantile esotropia manifests within 6 months of life, usually with a large-angle deviation (.30Δ), which was not present in our case. Moreover, infantile esotropia with predominantly torsional intermittent nystagmus is rare; therefore, individuals demonstrating torsional nystagmus with pathological head nodding are often referred urgently for neuroimaging to eliminate the presence of intracranial pathology. OCA can present with a large spectrum of phenotypical characteristics (1,2); however, OCA-related nystagmus typically has been described as horizontal with large amplitude and low frequency, with increasing slow-phase velocities. Torsional nystagmus associated with OCA has previously only been reported in one case. Summers et al (1996) described a 34-year-old Caucasian woman, with a molecular diagnosis of OCA, who presented with “rotary” nystagmus of small amplitude (5) At the time of presentation (.15 years ago), genetic testing was limited to single gene testing and HH-OCT had not yet been developed to facilitate pediatric Kuht et al: J Neuro-Ophthalmol 2023; 43: e313-e315 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Clinical Correspondence assessments. Diagnostic capabilities were therefore constrained to the available technologies at the time of presentation. The advances in genetic testing, and subsequent increased availability, have significantly aided diagnosis and management within ophthalmic settings, particularly with the introduction of a targeted NGS panel for infantile nystagmus (3). This high sensitivity and specificity panel includes all known nystagmus genes and assists cases where the clinical diagnosis is ambiguous or unknown, potentially negating the requirement for extensive clinical investigations. Our reported case is one such example where the nystagmus gene panel helped to consolidate the unusual clinical findings of intermittent torsional infantile nystagmus with head nodding and molecularly confirm the diagnosis of OCA. Results from the panel identified a known pathogenic mutation in TYR gene, in addition to the more recently reported pathogenic haplotype described by Gronskov et al (2018) (1). Furthermore, the recent advent of HH-OCT has facilitated the assessment of foveal morphology in younger children, thus providing improved diagnostic capabilities. In conclusion, we report a rare case of an individual presenting with intermittent torsional nystagmus, infantile Kuht et al: J Neuro-Ophthalmol 2023; 43: e313-e315 esotropia, and head nodding, with a molecularly confirmed diagnosis of OCA, thus expanding on the reported OCA phenotypes. Further genotype–phenotype studies would be useful to help with the understanding of pathophysiology of infantile torsional nystagmus. REFERENCES 1. Gronskov K, Jespersgaard C, Bruun GH, Harris P, BrondumNielsen K, Andresen BS, Rosenberg T. A pathogenic haplotype, common in Europeans, causes autosomal recessive albinism and uncovers missing heritability in OCA1. Sci Rep. 2019;9:645. 2. Thomas MG, Kumar A, Mohammad S, Proudlock FA, Engle EC, Andrews C, Chan WM, Thomas S, Gottlob I. Structural grading of foveal hypoplasia using spectral-domain optical coherence tomography a predictor of visual acuity? Ophthalmology. 2011;118:1653–1660. 3. Thomas MG, Maconachie G, Sheth V, McLean RJ, Gottlob I. Development and clinical utility of a novel diagnostic nystagmus gene panel using targeted next-generation sequencing. Eur J Hum Genet. 2017;25:725–734. 4. Brodsky MC, Wright KW. Infantile esotropia with nystagmus: a treatable cause of oscillatory head movements in children. Arch Ophthalmol. 2007;125:1079–1081. 5. Summers CG, Oetting WS, King RA. Diagnosis of oculocutaneous albinism with molecular analysis. Am J Ophthalmol. 1996;121:724–726. e315 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.